PROJECT SUMMARY Degeneration of the retinal pigment epithelium (RPE) is a pathological event commonly seen in various retinal diseases such as age-related macular degeneration and retinitis pigmentosa. The RPE is part of the outer blood retinal barrier that separates choroidal blood supply from the neurosensory retina. RPE injury activates retinal and choroidal compartment immune cells. The responses can either promote repair and recovery of the epithelium, or cause further tissue damage and immune pathology. Mechanisms controlling inflammation and immune functions in the outer retina and choroid are largely unclear. Clarifying the interactions between the RPE and immune cells is crucial for a better understanding of disease development and progression. ?? T cells are a group of unconventional, innate-like lymphocytes with potent effects on cell-mediated immunity near the epithelial barrier. We found that choroidal ?? T cells have novel protective functions in response to RPE injury through their functional interactions with the RPE. ?? T cell-deficient mice show increased sensitivity to sodium iodate-induced RPE damage and retinal toxicity; adoptive transfer of ?? T cells reverses this sensitization. Immune regulatory cytokines, such as interleukins 4, 10 and 17, are produced by choroidal ?? T cells via aryl hydrocarbon receptor (AhR)-dependent mechanisms. Accordingly, adoptive transfer of AhR- deficient ?? T cells is not protective against RPE injury in the sodium iodate model. Based on the findings from our published and preliminary studies, in the current proposal we hypothesize that choroidal ?? T lymphocytes regulate tissue homeostasis in the outer retina via AhR-dependent mechanisms. Three specific aims will be used to test the hypothesis. Aim 1 is to characterize choroidal ?? T cell function during chronic RPE degeneration conditions. Aim 2 is to determine the mechanistic role of AhR in activation of choroidal ?? T cells and their production of regulatory cytokines. Aim 3 is to determine whether modulating AhR activity by dietary phytochemicals will influence the protective effects of choroidal ?? T cells against RPE degeneration. The results from the proposed studies will define whether enhancing choroidal ?? T cell function is potentially a novel interventional strategy for treating retinal diseases that involve RPE degeneration.